N-benzyldioxothiazolidylbenzamide derivatives and process for producing the same

ABSTRACT

The present invention provides novel N-benzyldioxothiazolidylbenzamide derivatives that improve the insulin resistance and have potent hypoglycemic and lipid-lowering effects and processes for preparing the same, and relates to N-benzyldioxothiazolidylbenzamide derivatives characterized by being represented by a general formula (1) ##STR1## [wherein R 1  and R 2  denote identically or differently hydrogen atoms, lower alkyl groups with carbon atoms of 1 to 4, lower alkoxy groups with carbon atoms of 1 to 3, lower haloalkyl groups with carbon atoms of 1 to 3, lower haloalkoxy groups with carbon atoms of 1 to 3, halogen atoms, hydroxyl groups, nitro groups, amino groups which may be substituted with lower alkyl group(s) with carbon atoms of 1 to 3 or hetero rings, or R 1  and R 2  link to form a methylenedioxy group, R 3  denotes a lower alkoxy group with carbon atoms of 1 to 3, hydroxyl group or halogen atom, and dotted line indicates double bond or single bond in combination with solid line], and processes for preparing the same.

This application is a continuation of application Ser. No. 08/952,672filed on Dec. 2, 1997, now U.S. Pat. No. 6,030,990, pending, which wasoriginally filed as International Application No. PCT/JP96/01459, filedon May 30, 1996.

TECHNICAL FIELD

The present invention relates to novel N-benzyldioxothiazolidylbenzamidederivatives that improve the diabetes mellitus and the hyperlipidemia,and processes for preparing the same.

BACKGROUND TECHNOLOGIES

So far, as oral therapeutic drugs for diabetes mellitus, biguanide typeand sulfonylurea type compounds have been used. However, with biguanidetype compounds, lactic acidosis or hypoglycemia is caused and, withsulfonylurea type compounds, serious and prolonged hypoglycemia iscaused, and the adverse effect thereof is posing a problem, hence theappearance of new therapeutic drug for diabetes mellitus without suchdefects is desired. It is also known that some of thiazolidine-2,4-dionederivatives exhibit hypoglycemic and lipid-lowering effects (Journal ofMedicinal Chemistry, Vol. 35, P. 1853 (1992), Published UnexaminedPatent Application No. Hei 1-272573), but, in all of these compounds,the substituted position of middle benzene ring that connectsthiazolidine-2,4-dione ring and aromatic ring is p-position, or themiddle benzene ring has no substituent, further the aromatic ring of theformer is oxazol ring, the linkage of the latter is through sulfonamide,and the like, which differ structurally from compounds of the invention,N-benzyldioxothiazolidylbenzamide derivatives.

For the non-insulin dependent diabetes mellitus (NIDDM) accounting forthe majority of diabetics, a blood sugar-lowering drug that improves theinsulin resistance and has high safety and effectiveness is stronglydesired.

As a result of diligent studies on a drug that improves the insulinresistance and has potent hypoglycemic effects and high safety, theinventors have found that novel N-benzyldioxothiazolidylbenzamidederivatives represented by a following general formula (1) haveexcellent hypoglycemic and lipid-lowering effects, leading to thecompletion of the invention.

DISCLOSURE OF THE INVENTION

Namely, the invention provides N-benzyldioxothiazolidylbenzamidederivatives represented by a general formula (1) ##STR2## [wherein R¹and R² denote identically or differently hydrogen atoms, lower alkylgroups with carbon atoms of 1 to 4, lower alkoxy groups with carbonatoms of 1 to 3, lower haloalkyl groups with carbon atoms of 1 to 3,lower haloalkoxy groups with carbon atoms of 1 to 3, halogen atoms,hydroxyl groups, nitro groups, amino groups which may be substitutedwith lower alkyl group(s) with carbon atoms of 1 to 3 or hetero rings,or R¹ and R² link to form a methylenedioxy group, R³ denotes a loweralkoxy group with carbon atoms of 1 to 3, hydroxyl group or halogenatom, and dotted line indicates double bond or single bond incombination with solid line], and their pharmacologically acceptablesalts.

The salts of compounds represented by the general formula (1) in theinvention are of common use, and pharmacologically acceptable metalsalts such as alkali metal salts (e.g. sodium salt, potassium salt,etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt,etc.) and aluminum salt can be mentioned.

Moreover, the general formula (1) in the invention sometimes includesstereoisomers based on double bond and optical isomers based onthiazolidine portion. Such isomers and their mixtures are all to beincluded in the scope of this invention.

In the general formula (1) of the invention, for "lower alkyl group",straight or branched chain groups with carbon atoms of 1 to 4 such asmethyl, ethyl, propyl and butyl are mentioned.

For "lower alkoxy group", straight or branched chain groups with carbonatoms of 1 to 3 such as methoxy, ethoxy and propoxy are mentioned.

For "lower haloalkyl group", straight or branched chain groups withcarbon atoms of 1 to 3 such as trifluoromethyl are mentioned.

For "lower haloalkoxy group", straight or branched chain groups withcarbon atoms of 1 to 3 such as trifluoromethoxy are mentioned.

For "halogen atom", fluorine atom, chlorine atom, bromine atom andiodine atom are mentioned.

For "amino group which may be substituted with lower alkyl group", aminogroup, or methylamino group, ethylamino group, dimethylamino group,diethylamnino group, etc., in which one or two hydrogen atoms aresubstituted with straight or branched chain lower alkyl group withcarbon atoms of 1 to 3 such as methyl, ethyl and propyl, are mentioned.

According to the invention, compounds of said general formula (1) can beprepared through following processes.

Compounds of general formula (1) can be prepared by reacting compoundsof general formula (7) with compounds of general formula (11). ##STR3##[wherein R¹ and R² denote identically or differently hydrogen atoms,lower alkyl groups with carbon atoms of 1 to 4, lower alkoxy groups withcarbon atoms of 1 to 3, lower haloalkyl groups with carbon atoms of 1 to3, lower haloalkoxy groups with carbon atoms of 1 to 3, halogen atoms,hydroxyl groups, nitro groups, amino groups which may be substitutedwith lower alkyl group(s) with carbon atoms of 1 to 3 or hetero rings,or R¹ and R² link to form a methylenedioxy group, R³ denotes a loweralkoxy group with carbon atoms of 1 to 3, hydroxyl group or halogenatom, and dotted line indicates double bond or single bond incombination with solid line] ##STR4## [wherein R³ and dotted line are asdescribed above] ##STR5## [wherein R¹ and R² are as described above]

The reaction can be conducted by treating with condensing agent, forexample, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide, diethylcyanophosphate or the like in an organic solvent, for example, dimethylsulfoxide, N,N-dimethylformamide or the like. Moreover, if need be, anorganic base, for example, triethylamine or the like may be added.

As the reaction temperature, ice cooling to room temperature can beused.

Compounds of general formula (1b) can be prepared by reducing compoundsof general formula (1a). ##STR6## [wherein R¹, R² and R³ are asdescribed above] ##STR7## [where R¹, R² and R³ are as described above]

The reaction can be conducted by hydrogenating at ambient pressure to 4kg/cm² in the presence of catalyst such as palladium/carbon in anorganic solvent, for example, ethanol, ethyl acetate,N,N-dimethylformamide or the like or in a mixed solvent thereof at roomtemperature to heating. Or, it can be conducted by treating with sodiumamalgam in an organic solvent, for example, alcohol such as ethanol orin a mixed solvent with water at room temperature to heating.

Compounds of following general formula (1d) can be prepared by reactinggeneral formula (1c) with Lewis acid. ##STR8## [wherein R¹, R² anddotted line are as described above] ##STR9## [wherein R¹, R² and dottedline are as described above]

The reaction can be conducted by treating with Lewis acid, for example,boron tribromide, boron trichloride or the like in an organic solvent,for example, dichloromethane, chloroform or the like at -78° C. to roomtemperature.

Compounds of general formula (7) can be prepared by hydrolyzingcompounds of following general formula (6) ##STR10## [wherein R³ anddotted line are as described above, and R⁵ denotes a lower alkyl groupwith carbon atoms of 1 to 3]

The reaction can be conducted under acidic or alkaline conditionemploying cooling to solvent refluxing as reaction temperature and, forexample, refluxing under heat in a mixed solvent of acetic acid withconcentrated hydrochloric acid is preferable.

Compounds of general formula (4) can be prepared by reacting compoundsof following general formula (2) with compound of formula (3). ##STR11##[wherein R³ is as described above, and R⁴ denotes a hydrogen atom orlower alkyl group with carbon atoms of 1 to 3] ##STR12## [wherein R³ andR⁴ are as described above] ##STR13##

The reaction can be conducted in an organic solvent, for example,benzene, toluene, xylene or the like at room temperature tosolvent-refluxing temperature as reaction temperature, but thesolvent-refluxing temperature is preferable. Moreover, as a catalyst,addition of secondary amine (piperidine or the like) or acetic acid salt(ammonium acetate or the like) and acetic acid is suitable.

Also, it can be conducted by heating together with base (sodium acetate,piperidine or the like) without solvent.

Compounds of general formula (5) can be prepared by reducing compoundsof general formula (4). ##STR14## [wherein R³ and R⁴ are as describedabove]

The reaction can be conducted by hydrogenating at ambient pressure to 4kg/cm² in the presence of catalyst such as palladium/carbon in anorganic solvent, for example, ethanol, ethyl acetate,N,N-dimethylformamide or the like or in a mixed solvent thereof at roomtemperature to heating.

Or, it can be conducted by treating with sodium amalgam in an organicsolvent, for example, alcohol such as ethanol or in a mixed solvent withwater at room temperature to heating.

Compounds of general formula (7a) can be prepared by reacting compoundsof following general formula (10) with thiourea, followed by hydrolysis.##STR15## [wherein R³ is as described above] ##STR16## [wherein R³ andR⁵ are as described above, R⁶ denotes a lower alkyl group with carbonatoms of 1 to 3, and X denotes a halogen atom]

The reaction between compounds of general formula (10) and thiourea canbe conducted in an organic solvent, for example, alcohol such as ethanolat room temperature to solvent refluxing temperature, but the solventrefluxing temperature is preferable. If need be, a base (sodium acetateor the like) may be added. Successive hydrolysis reaction can beconducted under acidic condition and, for example, it is preferable toreflux under heat in hydrochloric acid or in a mixed solvent ofhydrochloric acid with organic solvent (sulforane or the like).

Compounds of general formula (10) can be prepared by convertingcompounds of general formula (8) to diazonium salts and then conductingMeerwein arylation with compounds of general formula (9). ##STR17##[wherein R³ and R⁵ are as described above] ##STR18## [wherein R⁶ is asdescribed above]

The reaction can be conducted by diazotizing compounds of generalformula (B) with nitrite such as sodium nitrite in an organic solvent,for example, alcohol such as methanol or ethanol, ketone such as acetoneor methyl ethyl ketone or water or in a mixed solvent thereof in thepresence of hydrogen halide such as hydrochloric acid or hydrobromicacid, and then reacting with catalytic amount of cuprous salt such ascuprous oxide or cuprous chloride in the presence of compounds ofgeneral formula (9)

In following, the invention will be illustrated based on concreteexamples, but the invention is not confined to these examples. Theabbreviated terms used in examples represent following meanings.

    ______________________________________                                        .sup.1 H NMR                                                                              Proton nuclear magnetic resonance spectrum                        MS          Mass spectrum                                                     CDCl.sub.3  Deuterated chloroform                                             DMF         N,N-dimethylformamide                                             DMSO        Dimethyl sulfoxide                                                THF         Tetrahydrofuran                                                   d.sub.6 -DMSO                                                                             Deuterated dimethyl sulfoxide                                     ______________________________________                                    

EXAMPLE 1

Methyl 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzoate

A mixture of methyl 5-formyl-2-methoxybenzoate (490 mg),thiazolidine-2,4-dione (358 mg), ammonium acetate (401 mg), acetic acid(0.8 ml) and benzene (10 ml) was submitted to Dean-Stalk dewateringapparatus to reflux for 4 hours under heat. After cooling, the crystalsdeposited were collected by filtration, washed with benzene and with 20%aqueous solution of acetone, and then dried to obtain 634 mg (86%) ofaimed compound as crystals.

¹ H NMR (d₆ -DMSO), δ:3.83(3 H, s), 3.90(3 H, s), 7.34(1 H, d, J 9.3Hz), 7.79(1 H, s), 7.76-7.83(1 H, m), 7.87-7.92(1 H, m), 12.59(1 H, s)

EXAMPLES 2 AND 3

Similarly to Example 1, compounds in Table 1 were obtained.

                  TABLE 1                                                         ______________________________________                                         ##STR19##                                                                    Example   R.sup.3                                                                              R.sup.4  Property                                                                             MS(m/z): M.sup.+                             ______________________________________                                        2         EtO    Et       Crystal                                                                              --                                           3         i-PrO  H        Crystal                                                                              307                                          ______________________________________                                    

EXAMPLE 4

Methyl 5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxy-benzoate

Methyl 5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxy-benzoate (9.52g) was suspended into DMF (250 ml) and hydrogenated with 10%palladium/carbon (10.0 g) at room temperature under a hydrogen pressureof 3.5 kg/cm². After the reaction, the solution was filtered andconcentrated and water was added to the residue, which was extractedwith ethyl acetate. The organic layer was washed with saturated brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by means of silica gel columnchromatography (developing solvent; methylene chloride:acetone=50:1) toobtain 5.88 g (61%) of aimed compound as an amorphous material.MS(m/z):295(M⁺)

EXAMPLE 5

5-(2,4-Dioxothiazolidin-5-ylidene)methyl-2-methoxy-benzoic acid

A suspension of methyl5-(2,4-dioxothiazolidin-5-ylidene)-methyl-2-methoxybenzoate (629 mg) inacetic acid-concentrated hydrochloric acid (1:1, 18.0 ml) was refluxedfor 6 hours under heat. After cooling, water (36 ml) was added and thecrystals were collected by filtration, washed with water and dried toobtain 599 mg (100%) of aimed compound as crystals.

¹ H NMR (d₆ -DMSO), δ:3.89(311, s), 7.31(1 H, d, J=8.8 Hz), 7.76 (1 H,dd, J=2.4, 8.8 Hz), 7.79(1 H, s), 7.89(1 H, d, J=2.4 Hz), 12.58(1 H, s),12.91(1 H, br)

EXAMPLES 6 AND 7

Similarly to Example 5, compounds in Table 2 were obtained.

                  TABLE 2                                                         ______________________________________                                         ##STR20##                                                                                   Dotted line                                                    Example R.sup.3                                                                              portion     Property                                                                             MS(m/z): M.sup.+                            ______________________________________                                        6       MeO    Single bond Crystal                                                                              --                                          7       Eto    Double bond Crystal                                                                              293                                         ______________________________________                                    

EXAMPLE 8

Methyl 2-bromo-3-(3-methoxycarbonyl-4-fluorophenyl)-propionate

To a solution of methyl 5-amino-2-fluorobenzoate (4.12 g) in 47%hydrobromic acid (11.4 ml), methanol (20 ml) and acetone (50 ml), asolution of sodium nitrite (1.88 g) in water (3 ml) was slowly addeddropwise under cooling with salt-ice and stirring so as to keep aninternal temperature of not higher than -5° C. After stirred for 30minutes as it was, ice bath was removed, methyl acrylate (13.3 ml) wasadded, and cuprous oxide (225 mg) was added little by little whilestirring vigorously. After no nitrogen became to generate, the reactionliquor was concentrated under reduced pressure. The residue wasdissolved into ethyl acetate, washed with water, saturated aqueoussolution of sodium hydrogencarbonate and water in order, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by means of silica gel column chromatography(developing solvent; n-hexane:ethyl acetate=10:1) to obtain 3.48 g (45%)of aimed compound as an oily material.

¹ H NMR (CDCl₃), δ:3.25(1 H, dd, J=7.3, 14.6 Hz), 3.46(1 H, dd, J=7.8,14.2 Hz), 3.75(3 H, s), 3.93(3 H, s), 4.38(1 H, t, J=7.8 Hz), 7.09(1 H,dd, J=8.8, 10.8 Hz), 7.38(1 H, ddd, J=2.4, 4.4, 8.8 Hz), 7.80(1 H, dd,J=2.4, 6.3 Hz) MS(m/z):318, 320(M⁺)

EXAMPLES 9 AND 10

Similarly to Example 8, compounds in Table 3 were obtained.

                  TABLE 3                                                         ______________________________________                                         ##STR21##                                                                    Example                                                                              R.sup.3   R.sup.5                                                                             R.sup.6                                                                             Property                                                                             MS(m/z): M.sup.+                          ______________________________________                                        9      6-MeO     Et    Me    Oily   344                                                                    material                                         10     2-MeO     Me    Me    Oily   330, 332                                                               material                                         ______________________________________                                    

EXAMPLE 11

5-(2,4-Dioxothiazolidin-5-yl)methyl-2-fluorobenzoic acid

To a solution of methyl2-bromo-3-(3-methoxycarbonyl-4-fluorophenyl)propionate (1.22 g) inethanol (40 ml), thiourea (356 mg) was added and the mixture wasrefluxed for 11 hours under heat. After cooling, this was concentratedunder reduced pressure and water (50 ml) was added to the residue. AfterpH was adjusted to around 8 with saturated aqueous solution of sodiumbicarbonate under stirring, ether (20 ml) and n-hexane (40 ml) wereadded, which was stirred for 10 minutes as it was. The crystals werecollected by filtration, washed with water, and then dried. The solidsthus obtained were dissolved into sulforane (10 ml) and, after 6Nhydrochloric acid (20 ml) was added, the mixture was refluxed for 8hours under heat. After cooling, this was poured into ice water and thecrystals deposited were collected by filtration, washed with water, andthen dried to obtain 403 mg (39%) of aimed compound as crystals.

¹ H NMR (d₆ -DMSO), δ:3.22(1 H, dd, J=8.3, 14.2 Hz), 3.51(,H, dd, J=4.4,14.2 Hz), 4.95(1 H, dd, J=4.4, 8.3 Hz), 7.27(1 H, dd, J=8.3, 10.8 Hz),7.51(1 H, ddd, J=2.5, 4.9, 8.3 Hz), 7.74(1 H, dd, J=2.5, 6.8 Hz),12.05(1 H, s), 13.28(1 H, s) MS(m/z):269(M⁺)

EXAMPLES 12 AND 13

Similarly to Example 11, compounds in Table 4 were obtained.

                  TABLE 4                                                         ______________________________________                                         ##STR22##                                                                    Example  R.sup.3     Property MS(m/z): M.sup.+                                ______________________________________                                        12       4-MeO       Crystal  281                                             13       2-Meo       Crystal  281                                             ______________________________________                                    

EXAMPLE 14

N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzamide

To a solution of5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzoic acid (1.00 g)and 4-trifluoromethylbenzylamine (627 mg) in DMF (10 ml), diethylcyanophosphate (615 mg) and triethylamine (370 mg) were added at roomtemperature in an argon atmosphere under stirring, and the mixture wasstirred for 5 hours as it was. The reaction liquor was poured into icewater and the crystals deposited were collected by filtration, washedwith water, and then dried to obtain 1.31 g (84%) of aimed compound ascrystals. Further, these were recrystallized from ethanol to obtainpurified aimed compound as yellow prismatic crystals. Melting point210.0˜211.5° C.

Elemental analysis (%): For C₂₀ H₁₅ F₃ N₂ O₄ S

    ______________________________________                                                  C             H      N                                              ______________________________________                                        Calculated                                                                              55.04         3.46   6.42                                           Found     55.30         3.36   6.48                                           ______________________________________                                    

EXAMPLES 15 THROUGH 38

Similarly to Example 14, compounds in Table 5 and Table 6 were obtained.

                                      TABLE 5                                     __________________________________________________________________________     ##STR23##                                                                                                      Elemental                                                Dotted                                                                            Melting point (° C.)                                                                    analysis (%)                                Ex-          line                                                                              (Recrystallization                                                                     Composition                                                                           Calculated/Found                            ample                                                                             R.sup.1 · R.sup.2                                                         R.sup.3                                                                           portion                                                                           solvent) formula C  H  N                                     __________________________________________________________________________    15  H    6-MeO                                                                             Single                                                                            Amorphous                                                                              C.sub.19 H.sub.18 N.sub.2 O.sub.4 S                                                   61.61                                                                            4.90                                                                             7.56                                               bond                 61.94                                                                            5.10                                                                             7.35                                  16  H    6-MeO                                                                             Double                                                                            209.0˜212.0                                                                      C.sub.19 H.sub.16 N.sub.2 O.sub.4 S                                                   61.94                                                                            4.38                                                                             7.61                                               bond                                                                              (Suspended into  62.32                                                                            4.50                                                                             7.48                                                   hexane)                                                      17  3-CF.sub.3                                                                         6-MeO                                                                             Single                                                                            145.0˜147.0                                                                      C.sub.20 H.sub.17 F.sub.3 N.sub.2 O.sub.4                                             54.79                                                                            3.91                                                                             6.39                                               bond                                                                              (Ethyl acetate-  54.68                                                                            3.85                                                                             6.27                                                   hexane)                                                      18  3-CF.sub.3                                                                         6-MeO                                                                             Double                                                                            188.0˜190.0                                                                      C.sub.20 H.sub.15 F.sub.3 N.sub.2 O.sub.4                                             52.86                                                                            3.77                                                                             6.17                                               bond                                                                              (Ethanol)                                                                              H.sub.2 O                                                                             52.78                                                                            3.72                                                                             6.18                                  19  2-CF.sub.3                                                                         6-MeO                                                                             Single                                                                            179.0˜181.0                                                                      C.sub.20 H.sub.17 F.sub.3 N.sub.2 O.sub.4                                             54.79                                                                            3.91                                                                             6.39                                               bond                                                                              (Ethyl acetate-  54.58                                                                            3.98                                                                             6.30                                                   hexane)                                                      20  2-CF.sub.3                                                                         6-MeO                                                                             Double                                                                            197.0˜199.0                                                                      C.sub.20 H.sub.15 F.sub.3 N.sub.2 O.sub.4                                             54.47                                                                            3.55                                                                             6.35                                               bond                                                                              (Ethanol)                                                                              1/4H.sub.2 O                                                                          54.60                                                                            3.42                                                                             6.37                                  21  3,5-CF.sub.3                                                                       6-MeO                                                                             Double                                                                            237.0˜239.0                                                                      C.sub.21 H.sub.14 F.sub.6 N.sub.2 O.sub.4                                             49.12                                                                            2.95                                                                             5.46                                               bond                                                                              (DMF-ethanol)                                                                          1/2H.sub.2 O                                                                          49.04                                                                            3.01                                                                             5.43                                  22  4-t-Bu                                                                             6-MeO                                                                             Single                                                                            135.0˜136.0                                                                      C.sub.23 H.sub.26 N.sub.2 O.sub.4 S                                                   64.77                                                                            6.14                                                                             6.57                                               bond                                                                              (Ethyl acetate-  64.97                                                                            6.31                                                                             6.32                                                   hexane)                                                      23  4-t-Bu                                                                             6-MeO                                                                             Double                                                                            185.0˜188.0                                                                      C.sub.23 H.sub.24 N.sub.2 O.sub.4 S.                                                  62.62                                                                            5.92                                                                             6.33                                               bond                                                                              (Ethanol)                                                                              H.sub.2 O                                                                             62.85                                                                            5.94                                                                             6.15                                  24  4-CF.sub.3 O                                                                       6-MeO                                                                             Double                                                                            166.0˜168.0                                                                      C.sub.20 H.sub.15 F.sub.3 N.sub.2 O.sub.5                                             53.09                                                                            3.34                                                                             6.19                                               bond                                                                              (Ethanol)        52.83                                                                            3.68                                                                             5.88                                  25  4-MeO                                                                              6-MeO                                                                             Double                                                                            209.0˜211.0                                                                      C.sub.20 H.sub.18 N.sub.2 O.sub.5 S                                                   60.29                                                                            4.55                                                                             7.03                                               bond                                                                              (DMF-ethanol)    60.35                                                                            4.55                                                                             7.03                                  26  3,4-MeO                                                                            6-MeO                                                                             Single                                                                            Amorphous                                                                              C.sub.21 H.sub.22 N.sub.2 O.sub.6 S.                                                  57.99                                                                            5.21                                                                             6.44                                               bond         1/4H.sub.2 O                                                                          58.02                                                                            5.44                                                                             6.15                                  __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________                  Dotted                                                                            Melting point (° C.)                                                                    Elemental analysis (%)                     Ex-           line                                                                              (Recrystallization                                                                     Composition                                                                           Calculated/Found                           ample                                                                             R.sup.1 . R.sup.2                                                                   R.sup.3                                                                           portion                                                                           solvent) formula C  H   N                                   __________________________________________________________________________    27  3,4-methy-                                                                          6-MeO                                                                             Double                                                                            238.0˜241.0                                                                      C.sub.20 H.sub.16 N.sub.2 O.sub.6 S                                                   58.24                                                                            3.91                                                                              6.79                                    lenedioxy bond                                                                              (DMF-ethanol)    58.17                                                                            3.98                                                                              6.80                                28  4-F   6-MeO                                                                             Single                                                                            Amorphous                                                                              C.sub.19 H.sub.17 FN.sub.2 O.sub.4 S                                          ·                                                                            57.41                                                                            4.56                                                                              7.05                                              bond         1/2H.sub.2 O                                                                          57.12                                                                            4.61                                                                              7.24                                29  4-CF.sub.3                                                                          4-MeO                                                                             Single                                                                            204.0˜207.0                                                                      C.sub.20 H.sub.17 F.sub.3 N.sub.2 O.sub.4                                             54.79                                                                            3.91                                                                              6.39                                              bond                                                                              (Acetonitrile)   54.76                                                                            3.92                                                                              6.55                                30  3,4-methy-                                                                          4-MeO                                                                             Single                                                                            134.0˜137.0                                                                      C.sub.20 H.sub.18 N.sub.2 O.sub.6 S                                                   57.96                                                                            4.38                                                                              6.76                                    lenedioxy bond                                                                              (Methylene       57.78                                                                            4.41                                                                              6.74                                                  chloride)                                                   31  H     4-MeO                                                                             Single                                                                             95.0˜98.0                                                                       C.sub.19 H.sub.18 N.sub.2 O.sub.4 S                                                   59.85idot.                                                                       5.09                                                                              7.35                                              bond                                                                              (Ethanol)                                                                              3/5H.sub.2 O                                                                          59.79                                                                            5.18                                                                              7.37                                32  4-CF.sub.3                                                                          2-MeO                                                                             Single                                                                            197.0˜199.0                                                                      C.sub.20 H.sub.17 F.sub.3 N.sub.2 O.sub.4                                             54.79                                                                            3.91                                                                              6.39                                              bond                                                                              (Ethanol)        54.70                                                                            3.84                                                                              6.39                                33  4-CF.sub.3                                                                          6-EtO                                                                             Double                                                                            227.0˜229.0                                                                      C.sub.21 H.sub.17 F.sub.3 N.sub.2 O.sub.4 S                                   ·                                                                            54.90                                                                            3.95                                                                              6.10                                              bond                                                                              (DMF-ethanol)                                                                          1/2H.sub.2 O                                                                          54.83                                                                            3.82                                                                              5.98                                34  3,4-methy-                                                                          6-EtO                                                                             Double                                                                            213.0˜215.0                                                                      C.sub.21 H.sub.18 N.sub.2 O.sub.6 S                                                   59.14                                                                            4.25                                                                              6.57                                    lenedioxy bond                                                                              (DMF-ethanol)    58.99                                                                            4.32                                                                              6.70                                35  4-CF.sub.3                                                                          6-i-PrO                                                                           Double                                                                            231.0˜232.0                                                                      C.sub.22 H.sub.19 F.sub.3 N.sub.2 O.sub.4                                             56.89                                                                            4.12                                                                              6.03                                              bond                                                                              (Ethanol)        56.68                                                                            4.11                                                                              6.02                                36  4-CF.sub.3                                                                          6-F Single                                                                            145.0˜146.0                                                                      C.sub.19 H.sub.14 F.sub.4 N.sub.2 O.sub.3                                             53.52                                                                            3.31                                                                              6.57                                              bond                                                                              (Methylene       53.36                                                                            3.22                                                                              6.62                                                  chloride)                                                                              C.sub.21 H.sub.21 N.sub.3 O.sub.4 S                37  4-(Me).sub.2 N                                                                      6-MeO                                                                             Double                                                                            203.0˜208.0                                                                              *                                                        bond                                                                              (Washed with                                                                  ethanol)                                                    38  4-Me  6-MeO                                                                             Double                                                                            170.0˜172.0                                                                      C.sub.20 H.sub.18 N.sub.2 O.sub.4 S                                                   MS (m/z) 382 (M.sup.+)                                   bond                                                                              (Ethanol)                                                   __________________________________________________________________________     * .sup.1 H NMR (d.sub.6 -DMSO), δ:2.86(6H, s), 3.94(3H, s), 4.38(2H     d, J = 5.9Hz), 6.69(2H, d, J = 8.8Hz), 7.18(2H, d, J = 8.8Hz), 7.28(1H, d     J = 7.9Hz), 7.74(1H, dd, J = 2,2,7.9Hz), 7.78(1H, s), 7.95(1H, d, J =         2.2Hz), 8.59(1H, t, J = 5.9Hz), 12.30(1H, br)                            

EXAMPLE 39

N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide

N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-ylidene)methyl-2-methoxybenzamide(500 mg) was suspended into ethanol (70 ml) and hydrogenated with 10%palladium/carbon (500 mg) at room temperature under a hydrogen pressureof 3.0 kg/cm². The reaction liquor was filtered and concentrated and theresidue was purified by means of silica gel column chromatography(developing solvent; methylene chloride:methanol=50:1) to obtain 403 mg(80%) of aimed compound as crystals. Further, these were recrystallizedfrom ethyl acetate to obtain purified aimed compound as colorlesspowdery crystals. Melting point 176.0˜177.5° C.

Elemental analysis (%): For C₂₀ H₁₇ F₃ N₂ O₄ S

    ______________________________________                                                  C             H      N                                              ______________________________________                                        Calculated                                                                              54.79         3.91   6.39                                           Found     54.75         3.84   6.40                                           ______________________________________                                    

EXAMPLES 40 THROUGH 48

Similarly to Example 39, compounds in Table 7 were obtained.

                                      TABLE 7                                     __________________________________________________________________________     ##STR24##                                                                                                   Elemental                                                    Melting point (° C.)                                                                    analysis (%)                                   Ex-           (Recrystallization                                                                     Composition                                                                           Calculated/Found                               ample                                                                             R.sup.1 · R.sup.2                                                          R.sup.3                                                                           solvent) formula C  H  N                                        __________________________________________________________________________    40  3.5-CF.sub.3                                                                        6-MeO                                                                             167.0˜169.0                                                                      C.sub.21 H.sub.16 F.sub.6 N.sub.2 O.sub.4 S                                           49.80                                                                            3.19                                                                             5.53                                                   (Ethanol)        50.00                                                                            3.06                                                                             5.54                                     41  4-Me  6-MeO                                                                             Amrphous C.sub.20 H.sub.20 N.sub.2 O.sub.4 S                                                   62.48                                                                            5.24                                                                             7.29                                                                    62.20                                                                            5.23                                                                             7.30                                     42  4-CF.sub.3 O                                                                        6-MeO                                                                             Amorphous                                                                              C.sub.20 H.sub.17 F.sub.3 N.sub.2 O.sub.5 S                                           52.86                                                                            3.77                                                                             6.17                                                                    52.68                                                                            3.80                                                                             6.45                                     43  4-MeO 6-MeO                                                                             Amorphous                                                                              C.sub.20 H.sub.20 N.sub.2 O.sub.5 S.                                                  59.31                                                                            5.11                                                                             6.92                                                            1/4H.sub.2 O                                                                          59.24                                                                            5.03                                                                             6.94                                     44  3,4-methy-                                                                          6-MeO                                                                             Amorphous                                                                              C.sub.20 H.sub.18 N.sub.2 O.sub.6 S.                                                  57.33                                                                            4.46                                                                             6.69                                         lenedioxy          1/4H.sub.2 O                                                                          57.10                                                                            4.38                                                                             6.89                                     45  4-(Me).sub.2 N                                                                      6-MeO                                                                             Amorphous                                                                              C.sub.21 H.sub.23 N.sub.3 O.sub.4 S.                                                  60.33                                                                            5.68                                                                             10.05                                                           1/4H.sub.2 O                                                                          60.48                                                                            5.66                                                                             10.13                                    46  4-CF.sub.3                                                                          6 -EtO                                                                            159.0˜162.0                                                                      C.sub.21 H.sub.19 F.sub.3 N.sub.2 O.sub.4 S                                           55.74                                                                            4.23                                                                             6.19                                                   (Ethanol)        55.65                                                                            4.25                                                                             6.34                                     47  3,4-methy-                                                                          6-EtO                                                                             Amorphous                                                                              C.sub.21 H.sub.20 N.sub.2 O.sub.6 S                                                   58.87                                                                            4.71                                                                             6.54                                         lenedioxy                  58.59                                                                            4.85                                                                             6.72                                     48  4-CF.sub.3                                                                          6-i-PrO                                                                           158.0˜158.5                                                                      C.sub.22 H.sub.21 F.sub.3 N.sub.2 O.sub.4 S                                           56.65                                                                            4.54                                                                             6.01                                                   (Ethyl acetate-  56.70                                                                            4.44                                                                             5.98                                                   hexane)                                                         __________________________________________________________________________

EXAMPLE 49

N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-hydroxybenzamide

To a suspension ofN-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide(800 mg) in anhydrous methylene chloride (30 ml), a 1.0N borontribromide-methylene chloride solution (2.20 ml) was slowly addeddropwise in an argon atmosphere under cooling with dry ice-acetone andstirring. After stirred for 6 hours at room temperature, the reactionliquor was allowed to stand for 3 days. After water was added and themixture was stirred for 30 minutes, this was concentrated under reducedpressure. Ethyl acetate was added to the residue, which was washed withwater and then dried over anhydrous sodium sulfate. This wasconcentrated under reduced pressure and the residue was purified bymeans of silica gel column chromatography (developing solvent; methylenechloride:methanol=40:1) to obtain 618 mg (80%) of aimed compound ascrystals. These were recrystallized from ethanol-water to obtainpurified aimed compound as a light brown powdery crystals. Melting point146.0˜148.0° C.

Elemental analysis (%): For C₁₉ H₁₅ F₃ N₂ O₄ S

    ______________________________________                                                  C             H      N                                              ______________________________________                                        Calculated                                                                              53.77         3.56   6.60                                           Found     53.92         3.88   6.49                                           ______________________________________                                    

EXAMPLE 50

(-)-N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide

Into 20 ml of ethyl acetate, 1.00 g of(±)-N-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamideobtained in Example 39 was dissolved under heat. After cooling, 0.276 gof L(-)-phenethylamine were added and the mixture was allowed to standfor a week at room temperature. The crystals deposited were filtered,washed with ethyl acetate and dried to obtain 0.753 g ofL(-)-phenethylamine salt as white flaky crystals. Further, these wererecrystallized from ethyl acetate to obtain 0.142 g of second crystalsand 0.0908 g of third crystals. Melting point 191˜193° C., Opticalrotation [α]_(D) =-87° (C=0.24, THF)

Elemental analysis (%): For C₂₈ H₂₈ F₃ N₃ O₄ S

    ______________________________________                                                  C             H      N                                              ______________________________________                                        Calculated                                                                              60.10         5.04   7.51                                           Found     60.24         5.05   7.43                                           ______________________________________                                    

To 20 ml of 1N hydrochloric acid, 0.753 g of first crystals were addedunder ice cooling. The mixture was stirred for 5 minutes and thenfiltered, and the crystals were washed with water and dried by heating.The crystals thus obtained were recrystallized from ethanol to obtain0.532 g of aimed product as white powdery crystals. Melting point194˜195° C., Optical rotation [α]_(D) =-100° (C=0.24, THF)

Elemental analysis (%): For C₂₀ H₁₇ F₃ N₂ O₄ S

    ______________________________________                                                  C             H      N                                              ______________________________________                                        Calculated                                                                              54.79         3.91   6.39                                           Found     54.72         3.90   6.35                                           ______________________________________                                    

For measuring the optical purity, part of crystals obtained (ca. 1 mg)was sampled and dissolved into 3 ml of methanol. After cooling, 0.2 mlof diazomethane-ether solution were added and, after stirred for 5minutes at room temperature, solvent was distilled off under reducedpressure. Further, after distilled off the residual solvent for one hourwith pump for distillation under reduced pressure, the residue wasdissolved into methanol, and the optical purity was measured by means ofliquid chromatography (column; chiral cell AD (Daicel), eluting solvent;hexane:isopropanol=70:30, flow rate; 1.0 ml/min, measuring wavelength;λ=230 nm, retention time; 22.31 min) to obtain 99.2% ee.

EXAMPLE 51

(+)-N-(4-Trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide

Similarly to Example 50, 1.00 g of(±)-N-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidine-5-yl)methyl-2-methoxybenzamideobtained in Example 39 was submitted to the optical resolution withD(+)-phenethylamine to obtain 0.742 g of first crystals, 0.143 g ofsecond crystals and 0.0587 g of third crystals as white flaky crystalsfor D(+)-phenethylamine salt. Melting point 191˜193° C., Opticalrotation [α]_(D) =87° (C=0.24, THF)

Elemental analysis (%): For C₂₈ H₂₈ F₃ N₃ O₄ S

    ______________________________________                                                  C             H      N                                              ______________________________________                                        Calculated                                                                              60.10         5.04   7.51                                           Found     59.95         5.19   7.49                                           ______________________________________                                    

Similarly to Example 50, 0.742 g of first crystals were treated with 1Nhydrochloric acid and recrystallized from ethanol to obtain 0.510 g ofaimed product as white powdery crystals. Melting point 194˜195° C.,Optical rotation [α]_(D) =100° (C=0.24, THF)

Elemental analysis (%): For C₂₀ H₁₇ F₃ N₂ O₄ S

    ______________________________________                                                  C             H      N                                              ______________________________________                                        Calculated                                                                              54.79         3.91   6.39                                           Found     54.88         4.03   6.42                                           ______________________________________                                    

For measuring the optical purity, N-methylation was made withdiazomethane similarly to Example 50, and then the optical purity wasmeasured by means of liquid chromatography (column; chiral cell AD(Daicel), eluting solvent; hexane:isopropanol=70:30, flow rate; 1.0ml/min, measuring wavelength; λ=230 nm, retention time; 30.64 min) toobtain 99.2% cc.

Test example 1

Employing inherited obese mice (C57BL ob/ob), the value of blood sugarwas determined by collecting blood from caudal vein prior to testing.They were grouped so as not to cause any difference in the values ofblood sugar, and the compounds of Example 36, 39, 46 and 48 wereadministered orally for 5 days at a dosage of 10 mg/kg, respectively.For the glucose resistance test, 2 g/kg of glucose were administeredorally after fasted overnight and the values of blood sugar at 0 minute,30 minutes and 60 minutes were determined. The blood sugar-lowering ratewas calculated from following formula. ##EQU1##

Results are shown in Table 8. From these results, it was shown that theinventive compounds had potent hypoglycemic effects.

                  TABLE 8                                                         ______________________________________                                                               Blood sugar-                                                          Dosage  lowering rate                                          Compound       (mg/kg) (%)                                                    ______________________________________                                        Example 36     10      43                                                     Example 39     10      47                                                     Example 46     10      37                                                     Example 48     10      45                                                     ______________________________________                                    

Test example 2

Employing inherited obese mice (C57BL ob/ob), value of triglyceride inblood and value of free fatty acid in blood were determined bycollecting blood from caudal vein prior to testing and they weregrouped. After the compound of Example 39 was administered orally for 2weeks at following dosages, the value of triglyceride in blood and thevalue of free fatty acid in blood were determined. The lowering rate ofeach parameter was calculated from following formula. ##EQU2##

Results are shown in Table 9. From these results, it was shown that theinventive compound had potent lipid-lowering effects.

                  TABLE 9                                                         ______________________________________                                                         Lowering rate of tri-                                                                      Lowering rate of free                                   Dosage   glyceride in blood                                                                         fatty acid in blood                             Compound                                                                              (mg/kg)  (%)          (%)                                             ______________________________________                                        Example 39                                                                            1        28           26                                                      3        42           29                                              ______________________________________                                    

As above, with the N-benzyldioxothiazolidylbenzamide derivatives inaccordance with the invention, drugs that improve the insulin resistancein the non-insulin dependent type diabetes mellitus and have potenthypoglycemic effects and high safety can be obtained.

What is claimed is:
 1. A method of treating hyperglycemia whichcomprises administering to a patient in need thereof, in an amounteffective to lower the blood sugar level of said patient, anN-benzyldioxothiazolidylbenzamide compound of the formula: ##STR25##wherein R¹ and R² denote identically or differently hydrogen atoms,lower alkyl groups with carbon atoms of 1 to 4, lower alkoxy groups withcarbon atoms of 1 to 3, lower haloalkyl groups with carbon atoms of 1 to3, lower haloalkoxy groups with carbon atoms of 1 to 3, halogen atoms,hydroxyl groups, nitro groups, amino groups optionally substituted withlower alkyl group(s) with carbon atoms of 1 to 3 or hetero rings, or R¹and R² link to form a methylenedioxy group, R³ denotes a lower alkoxygroup with carbon atoms of 1 to 3, hydroxyl group or halogen atom, anddotted line indicates double bond or single bond in combination withsolid line, or a pharmacologically acceptable salt thereof.
 2. A methodaccording to claim 1 wherein said compound comprisesN-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-methoxybenzamide,or a pharmacologically acceptable salt thereof.
 3. A method according toclaim 1 wherein said compound comprisesN-(4-trifluoromethylbenzyl)-5-(-2,4-dioxothiazolidin-5-yl)methyl-2-isopropoxybenzamide,or a pharmacologically acceptable salt thereof.
 4. A method according toclaim 1 wherein said compound comprisesN-(4-trifluorornethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-ethoxybenzamide,or a pharmacologically acceptable salt thereof.
 5. A method according toclaim 1 wherein said compound comprisesN-(4-trifluoromethylbenzyl)-5-(2,4-dioxothiazolidin-5-yl)methyl-2-fluorobenzamide,or a pharmacologically acceptable salt thereof.